Summary

Background

Lowering cholesterol in hypercholesterolemic patients with coronary artery disease has been shown to reduce recurrent events. The same has not been demonstrated clearly for patients with normal cholesterol levels. Since the majority of patients with coronary disease have cholesterol levels in the average range, this question is an important one. The Cholesterol and Recurrent Events Trial was designed to investigate this issue. Post-MI patients with average cholesterol levels were randomized to therapy with pravastatin or placebo and followed for an average of 5 years.

Methods

Subjects

Men and postmenopausal women, 21 to 75 years of age, recruited at 13 centers in Canada and 67 centers in the United States.

Total cholesterol less than 240 mg/dl; calculated LDL 115-174 mg/dl; triglycerides less than 350 mg/dl.

Plasma lipids were measured at least 8 weeks post MI and after 4 weeks of an NCEP step 1 diet; the average of 2 or 3 measurements was used.

Intervention

Patients were randomized to 40 mg of pravastatin daily or placebo. Lipids were measured at baseline and after 6 weeks, 12 weeks, quarterly for the first year and semi-annually thereafter. Clinical follow-up was quarterly.

If LDL was > 175, more intense (step 2) dietary counselling was given; if this was not sufficient, cholestyramine was added to the regimen. In order to maintain balance between the two groups, for every patient in one group given cholestyramine or dietary counselling, a sex and age-matched patient in the other group, in the highest decile of LDL cholesterol, was given the same therapy. If neither of these interventions was sufficient, the patient was referred to his or her physician for further treatment.

Endpoints

The primary endpoint was a combined endpoint: death from coronary heart disease (fatal MI, sudden death, death during a coronary intervention) or symptomatic, nonfatal MI.

Various coronary and non-coronary events were also recorded and reported such as death from CAD, nonfatal MI, fatal MI, coronary interventions, unstable angina, stroke, all-cause mortality, cancer incidence.

Results

Patients

4159 patients randomized in 1990 and 1991. Follow-up was until January, 1996 (mean: 5 years of follow-up).

Baseline characteristics were well matched. Some pertinent characteristics:

Cancer incidence: 7.7% vs. 8.3% (p=NS). There were 12 cases of breast cancer in the pravastatin group vs. 1 case in the placebo group (p=0.002), but of these 12, 4 were either pre-existing or occurred after only a short exposure to the drug and one was ductal in situ.

Effect in subgroups

The effect of pravastatin was examined in a number of subgroups. The outcome that was used was a combined outcome: death from CHD, nonfatal MI, CABG or PTCA.

For most subgroups, there was no significant difference. These included age (less than or greater than 60 years), hypertension, diabetes, current smoking, ejection fraction, prior CABG or PTCA, and type of MI (Q-wave or not).

The effect of pravastatin was greater in women (risk reduction 46%, vs. 20% in men).

Baseline LDL levels:

150 - 175 -- RR 35%

125 - 150 -- RR 26%

< 125 -- RR -3%

For baseline triglyceride levels greater than 144, the RR was 15%; for baseline triglycerides less than 144, the RR was 32%.

Authors' Discussion

The authors note that, in post-MI patients, reducing cholesterol levels from average values to around 100 mg/dl significantly reduced coronary events, although not overall mortality. This effect was seen in subgroups in which the benefit of lowering cholesterol was previously unclear (women, patients over 60). The relationship between baseline LDL and risk reduction is stressed -- the higher the baseline LDL level, the greater the risk reduction. Treating patients with baseline LDL's under 125 is probably not warranted.

The authors discuss the favorable effect of lipid-lowering therapy on the incidence of stroke. They argue against the importance of the increase in breast cancer, since the incidence in the placebo group was substantially lower than would have been expected, and other studies have failed to indicate a relation between breast cancer and statin therapy.

They calculate that, by treating 1000 patients for five years, 150 cardiovascular events could be prevented, and 51 patients could be prevented from having one or more events.

Comment

Once again (see "a note on combining endpoints" in the summary on digoxin in CHF), I don't think the combined endpoint "death from CHD or non-fatal MI" is particularly useful from a clinical standpoint, although it makes sense patho-physiologically. I believe the individual endpoints (MI, total mortality) are the most significant.

What are the main results of this study? In patients post-MI with average cholesterol levels, treatment for 5 years with a statin at a dose sufficient to lower LDL cholesterol from approximately 140 mg/dl to 100 mg/dl resulted in:

A reduction in non-fatal MI incidence from 11.1% to 8.7% (p=0.01). You would need to treat 42 patients for five years to avoid one non-fatal MI.

A reduction in the rate of CABG or PTCA from 18.8% to 14.1% (p<0.001). NNT= 21 patients treated for 5 years to avoid one procedure.

A reduction in stroke risk from 3.8% to 2.6% (p=0.03). NNT=83 patients.

How do these results fit in with the two other big statin trials, the Scandinavian Simvastatin Survival Study (4S) (1) and the West of Scotland study (WOSCOP) (2, and reviewed here)?

4S

CARE

WOSCOP

Patients

Secondary prevention.Post-MI with high cholesterol.

Secondary prevention.Post-MI with average cholesterol.

Primary prevention.High risk patients with high cholesterol.

LDL cholesterol reduction

From 188 to 122

From 139 to 98

From 192 to 142

Reduction in MI incidence

18.8% to 12.6%Absolute reduction: 6.2%

11.1% to 8.7%Absolute reduction: 2.4%

7.8% to 5.8%Absolute reduction: 2.0%

Reduction in total mortality

12% to 8%Absolute reduction: 4%

NS(9.4% to 8.7%)

4.1% to 3.2%Absolute reduction: 0.9% (p=0.051)

Reduction in CABG or angioplasty

17.2% to 11.3%Absolute reduction: 5.9%

18.8% to 14.1%Absolute reduction: 4.7%

2.5% to 1.7%Absolute reduction: 0.8%

Reduction in stroke rate

4.3% to 2.7% (includes TIA's)Absolute reduction 1.6%

3.8% to 2.6%Absolute reduction 1.2%

1.6% to 1.6%No change

Overall, this table seems to show that the cardiovascular risk and treatment benefit are highest for secondary prevention with high cholesterol, intermediate for secondary prevention with average cholesterol and lowest for primary prevention. This is as we would expect. The lack of effect on overall mortality in CARE, contrasted with the marginal effect found in WOSCOP may be due to the larger sample size in WOSCOP. The higher intervention rate (CABG and PTCA) in CARE is probably due to the fact that this was a North American trial.

March 12, 1997

Reader comments
Date: Sun, 6 Apr 1997
From: CPutnam815@aol.com

Do you feel that this is a definitely a result of the lowering of LDL
Cholesterol? Also, do you feel that this is a class effect? Would you be
comfortable using any statin to reduce mortality regardless of available
study or not?

Strictly speaking, studies only show what they show. For example, if a study demonstrates a 10% reduction in MI incidence in a given population with a specific drug, then we can assume with a certain degree of statistical confidence (depending on the p-value) that the same drug, given to a different subpopulation of the same population will have a similar effect.

Nevertheless, we make logical inferences from the data and act on these inferences. But, the greater the leap of these logical inferences, the greater the likelihood that they are wrong.

To take the case in point, the results demonstrate a beneficial effect of one of the statins (pravastatin) in post-MI patients. Applying the results directly, if we give pravastatin to a similar population of post-MI patients, we would expect to see grossly similar results. We assume that the reduction on LDL is the prime mechanism behind these results (based on other studies and on epidemiological evidence), but we cannot say that this study "proves" this.

Would these results apply to other statins? Probably, although there is always a small chance that there is something unique about the particular drug studied here. Would they apply to other types of cholesterol-lowering agents? Again, probably, but the chance is now higher that changing the class of agents will change the outcome.

The question of the degree to which a study only applies to a specific agent is an important one, since many studies are funded by pharmaceutical companies and look at specific, new agents with a long patent lifetime. Thus, only the higher priced, non-generic drugs can be officially said to produce the effect demonstrated by the study.

To what extent the practitioner can substitute one agent for another is, in final analysis, a question of belief, of common sense, and of other issues (such as cost and drug side-effects).

Personally, for a given change in LDL, HDL and triglycerides, I believe all of the statins are equivalent but that's just my own belief and bias. It's based on the fact that different statins have shown roughly comparable effects in clinical trials. But this doesn't prove their equivalence, just makes it more likely. -- mj